Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.
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PMID:Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. 1470 26

In the present study, the potential of selenium to enhance stem cell behavior through improvement of human adipose tissue-derived stromal cells (ATSCs) and the associated molecular mechanism was evaluated. Selenium-induced improvement in stem cell behavior of human ATSCs caused expression of several genes, indicating downregulated mature cell marker proteins coupled with increased cell growth and telomerase activities after the overexpression of Rex1, Nanog, OCT4, SOX2, KLF4, and c-Myc. Also, selenium-treated ATSCs significantly downregulated p53 and p21 tumor suppressor gene products. Selenium induced active growth and growth enhanced by the activation of signal proteins in ATSCs via the inhibition of reactive oxygen species-mediated phospho-stress-activated protein kinase/c-Jun N-terminal protein kinase activation. The selenium-induced activation of extracellular regulated kinases 1/2 and Akt in ATSCs resulted in a subsequent induction of the expression of stemness transcription factors, particularly Rex1, Nanog, and Oct4, along with definitive demethylation on regulatory regions of Rex-1, Nanog, and Oct4. The results of our small interfering RNA knockdown experiment showed that Rex1 plays a major role in the proliferation of selenium-induced ATSCs. Selenium-treated ATSCs also exhibited more profound differentiation into mesodermal and neural lineages. We performed a direct comparison of gene expression profiles in control ATSCs and selenium-treated ATSCs and delineated specific members of important growth factor, signaling, cell adhesion, and transcription factor families. The observations of improved life span and multipotency of selenium-treated ATSCs clearly indicate that selenium-treated ATSCs represent an extraordinarily useful candidate cell source for tissue regeneration. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:IFATS collection: Selenium induces improvement of stem cell behaviors in human adipose-tissue stromal cells via SAPK/JNK and stemness acting signals. 2473 3

Induced pluripotent stem (iPS) cells are generated from somatic cells by genetic manipulation. Reprogramming entails multiple transgene integrations and occurs apparently stochastically in rare cells over many days. Tissue stem cells may be subject to less-stringent epigenetic restrictions than other cells and might therefore be more amenable to deprogramming. We report that brain-derived neural stem (NS) cells acquire undifferentiated morphology rapidly and at high frequency after a single round of transduction with reprogramming factors. However, critical attributes of true pluripotency--including stable expression of endogenous Oct4 and Nanog, epigenetic erasure of X chromosome silencing in female cells, and ability to colonise chimaeras--were not attained. We therefore applied molecularly defined conditions for the derivation and propagation of authentic pluripotent stem cells from embryos. We combined dual inhibition (2i) of mitogen-activated protein kinase signalling and glycogen synthase kinase-3 (GSK3) with the self-renewal cytokine leukaemia inhibitory factor (LIF). The 2i/LIF condition induced stable up-regulation of Oct4 and Nanog, reactivation of the X chromosome, transgene silencing, and competence for somatic and germline chimaerism. Using 2i /LIF, NS cell reprogramming required only 1-2 integrations of each transgene. Furthermore, transduction with Sox2 and c-Myc is dispensable, and Oct4 and Klf4 are sufficient to convert NS cells into chimaera-forming iPS cells. These findings demonstrate that somatic cell state influences requirements for reprogramming and delineate two phases in the process. The ability to capture pre-pluripotent cells that can advance to ground state pluripotency simply and with high efficiency opens a door to molecular dissection of this remarkable phenomenon.
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PMID:Promotion of reprogramming to ground state pluripotency by signal inhibition. 2007 93

Reprogramming of nuclei allows the dedifferentiation of differentiated cells. Somatic cells can undergo epigenetic modifications and reprogramming through their fusion with embryonic stem cells (ESCs) or after overexpression of a specific blend of ESC transcription factor-encoding genes. We show here that cyclic activation of Wnt/beta-catenin signaling in ESCs with Wnt3a or the glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime (BIO) strikingly enhances the ability of ESCs to reprogram somatic cells after fusion. In addition, we show that reprogramming is triggered by a dose-dependent accumulation of active beta-catenin. Reprogrammed clones express ESC-specific genes, lose somatic differentiation markers, become demethylated on Oct4 and Nanog CpG islands, and can differentiate into cardiomyocytes in vitro and generate teratomas in vivo. Our data thus demonstrate that in ESCs, periodic beta-catenin accumulation via the Wnt/beta-catenin pathway provides a specific threshold that leads to the reprogramming of somatic cells after fusion.
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PMID:Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. 1898 57

C57BL/6 (B6)-derived embryonic stem (ES) cells are not widely used to generate knockout mice despite the advantage of a well-defined genetic background because of poor developmental potential. We newly established serum- and feeder-free B6 ES cells with full developmental potential by using leukemia inhibitory factor (LIF) and 6-bromoindirubin-3'-oxime (BIO), a glycogen synthase kinase-3 (GSK3) inhibitor. BIO treatment significantly increased the expression levels of 364 genes including pluripotency markers such as Nanog and Klf family. Unexpectedly, by aggregating or microinjecting those ES cells to each eight-cell-stage diploid embryo, we stably generated germline-competent ES-derived mice. Furthermore, founder mice completely derived from female XO, heterozygous, or homozygous mutant B6 ES cells were directly available for intercross breeding and phenotypic analysis. We hereby propose that serum- and feeder-free B6 ES cells stimulated with LIF plus GSK3 inhibitor are valuable for generating mouse models on B6 background.
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PMID:Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitor. 1939 Nov 15

At present, genetically modified rats have not been generated from ES cells because stable ES cells and a suitable injection method are not available. To monitor the pluripotency of rat ES cells, we generated Oct4-Venus transgenic (Tg) rats via a conventional method, in which Venus is expressed by the Oct4 promoter/enhancer. This monitoring system enabled us to define a significant condition of culture to establish authentic rat ES cells based on a combination of 20% FBS and cell signaling inhibitors for Rho-associated kinase, mitogen-activated protein kinase, TGF-beta, and glycogen synthase kinase-3. The rat ES cells expressed ES cell markers such as Oct4, Nanog, Sox2, and Rex1 and retained a normal karyotype. Embryoid bodies and teratomas were also produced from the rat ES cells. All six ES cell lines derived from three different rat strains successfully achieved germline transmission, which strongly depended on the presence of the inhibitors during the injection process. Most importantly, high-quality Tg rats possessing a correct transgene expression pattern were successfully generated via the selection of gene-manipulated ES cell clones through germline transmission. Our rat ES cells should be sufficiently able to receive gene targeting as well as Tg manipulation, thus providing valuable animal models for the study of human diseases.
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PMID:Generation of genetically modified rats from embryonic stem cells. 2066 Jul 26

Nanog is a key determinant that maintains self-renewal and pluripotency of embryonic stem cells and represses their differentiation to endoderm. In this study, we examined the regulation of Nanog expression by phosphoinositide-3-kinase (PI3K)/Akt pathway during retinoic acid (RA)-induced differentiation of F9 embryonic carcinoma cells. Nanog protein expression was transiently upregulated up to 6 h after RA treatment and then declined. In agreement, a murine Nanog promoter reporter assay revealed that promoter activity increased during early stage of differentiation, but decreased when F9 cells became fully differentiated. RA treatment of F9 cells also led to a transient and parallel increase in both Akt and glycogen synthase kinase 3beta phosphorylations. Nanog expression was diminished in the early stage by LY294002, a PI3K inhibitor, but was not affected in the late stage despite considerable inhibition of Akt phosphorylation and endoderm marker expression by the inhibitor. These data suggest that RA-induced PI3K/Akt activation in the early stage of differentiation is required for Nanog expression, which becomes independent of PI3K/Akt signaling once the differentiation is established. Thus, Nanog expression appears to be differently regulated by the PI3K/Akt pathway depending on differentiation stage.
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PMID:The phosphoinositide-3-kinase/Akt pathway mediates the transient increase in Nanog expression during differentiation of F9 cells. 2066 23

Mammalian aging of many tissues is associated with a decline in the replicative and functional capacity of somatic stem cells. Understanding the basis of this decline is a major goal of aging research. Human bone marrow-derived multipotent stromal cells (MSCs) have been applied in the treatment of fracture nonunion. Clinical application of MSCs requires abundant cells that can be overcome by ex vivo expansion of cells, but often at the expense of stemness and differentiation potentiality. We first demonstrated that late-passage MSCs exhibited decreased proliferation capacity, reduced expression of stemness markers such as Oct-4 and Nanog, and deterioration of osteogenic potential. Further, late-passage MSCs showed increased expression of p21(Cip1/Waf1) (p21), an inhibitor of the cyclin-dependent kinase. Knockdown of p21 by lentivirus-mediated shRNAs against p21 in late-passage MSCs increased the proliferation capacity, the expression of Oct-4 and Nanog, and osteogenic potential compared with cells transduced with control shRNA. More importantly, reduction in p21 expression in MSCs enhanced the bone repair capacity of MSCs in a rodent calvarial defect model. Knockdown of p21 in MSCs also increased the telomerase activity and telomere length, and did not show chromosomal abnormalities or acquire transformation ability. Therefore, these data successfully demonstrate the involvement of senescence gene in the expression of stemness markers and osteogenic potential of MSCs.
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PMID:Knockdown of p21(Cip1/Waf1) enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells. 2134 17

Self-renewal and pluripotency of embryonic stem (ES) cells are maintained by several signaling cascades and by expression of intrinsic factors, such as Oct4, Nanog and Sox2. The mechanism regulating these signaling cascades in ES cells is of great interest. Recently, we have demonstrated that natriuretic peptide receptor A (NPR-A), a specific receptor for atrial and brain natriuretic peptides (ANP and BNP, respectively), is expressed in pre-implantation embryos and in ES cells. Here, we examined whether NPR-A is involved in the maintenance of ES cell pluripotency. RNA interference-mediated knockdown of NPR-A resulted in phenotypic changes, indicative of differentiation, downregulation of pluripotency factors (such as Oct4, Nanog and Sox2) and upregulation of differentiation genes. NPR-A knockdown also resulted in a marked downregulation of phosphorylated Akt. Furthermore, NPR-A knockdown induced accumulation of ES cells in the G1 phase of the cell cycle. Interestingly, we found that ANP was expressed in self-renewing ES cells, whereas its level was reduced after ES cell differentiation. Treatment of ES cells with ANP upregulated the expression of Oct4, Nanog and phosphorylated Akt, and this upregulation depended on NPR-A signaling, because it was completely reversed by pretreatment with either an NPR-A antagonist or a cGMP-dependent protein kinase inhibitor. These findings provide a novel role for NPR-A in the maintenance of self-renewal and pluripotency of ES cells.
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PMID:NPR-A regulates self-renewal and pluripotency of embryonic stem cells. 2139 61

The effect of visible light irradiation on the expression of pluripotent genes (Oct-4, Sox2, and Nanog) in amniotic fluid-derived stem cells (AFSCs) and on the osteogenic differentiation ability of AFSCs was investigated using light-emitting diodes (LEDs) at 0-2 mW/cm(2) in various wavelengths: [blue (470 nm), green (525 nm), yellow (600 nm), and red (630 nm)]. Pluripotent gene expression in AFSCs was up-regulated by visible light irradiation from a LED for more than 6 h. Green light irradiation of AFSCs up-regulated the expression of pluripotent genes more significantly than irradiation with other light. The osteogenic differentiation of AFSCs was facilitated by green and blue light irradiation. Facilitated differentiation into osteogenic cells by visible light irradiation was not mediated by reactive oxygen species (ROS); alkaline phosphatase activity (a marker of early osteogenic differentiation) and gene expression of osteopontin (a marker of late osteogenic differentiation) did not change significantly between AFSCs in differentiation medium with or without a ROS scavenger (vitamin C). The mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway, as well as other unknown signaling pathways, may be responsible for the activation of signaling pathways that facilitate the differentiation of AFSCs into osteogenic cells on light irradiation.
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PMID:Osteoblast differentiation of amniotic fluid-derived stem cells irradiated with visible light. 2177 92


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